1,4-Dihydropyridine carboxylic acid esters

ABSTRACT

1,4-DIHYDROPYRIDINE CARBOXYLIC ACID ESTERS OF THE FORMULA: ##STR1##   or a pharmaceutically acceptable nontoxic salt thereof wherein R is hydrogen, straight- or branched-chain lower alkyl, lower alkenyl or lower alkynyl; 
     R 1  and R 4  are the same or different and are each hydrogen or straight- or branched-chain lower alkyl; 
     X is straight- or branched-chain lower alkylene; 
     Y is α-, β-, or γ-pyridyl, or the moiety NR&#39;R&#34; wherein 
     R&#39; and R&#34; are the same or different and are each hydrogen or lower alkyl, or 
     R&#39; and R&#34;, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring wherein said nitrogen atom is the only heteroatom, or a 5-, 6- or 7-membered heterocyclic ring which has at least one additional heteroatom selected from the group consisting of oxygen, sulphur, NH or N-(lower alkyl); 
     R 2  is aryl unsubstituted or substituted by 1, 2 or 3 substituents selected from the group consisting of nitro, cyano, azido, lower alkyl, lower alkoxy, lower acyloxy, carb-(lower alkoxy), amino, lower acylamino, lower alkylamino, di(lower alkylamino), SO n  -(lower alkyl) wherein n is 0, 1 or 2, phenyl, trifluoromethyl and halogen; benzyl; phenyl-ethyl; styryl; cycloalkyl; cycloalkenyl; or naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyrryl, furyl or thenyl unsubstituted or substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, nitro and halogen; and 
     R 3  is a straight- or branched-chain lower hydrocarbon unsubstituted or substituted by one or two hydroxyl groups, a straight- or branched-chain lower hydrocarbon interrupted by one or two oxygen atoms, the moiety --OQ wherein Q is straight, branched or cyclic, saturated, partially unsaturated or unsaturated lower hydrocarbon unsubstituted or substituted by one or two hydroxyl groups, a straight, branched or cyclic, saturated, partially unsaturated or unsaturated lower hydrocarbon interrupted by one or two oxygen atoms or the moiety --O--X&#39;--Y&#39; wherein X&#39; is straight- or branched-chain lower alkylene and 
     Y&#39; is α-, β- or γ-pyridyl, or the moiety NR&#39;R&#34; wherein 
     R&#39; and R&#34; are the same or different and are each hydrogen or lower alkyl or 
     R&#39; and R&#34;, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered heterocyclic ring wherein said nitrogen atom is the only heteroatom or a 5-, 6- or 7-membered heterocyclic ring which has at least one additional heteroatom selected from the group consisting of oxygen, sulphur, NH or N-(lower alkyl); 
     Are useful for their coronary activity, particularly as coronary vessel dilators and as antihypertensives.

This is a division of application Ser. No. 350,381 filed Apr. 12, 1973.

The present invention is concerned with 1,4-dihydropyridine carboxylicacid esters, processes for their production, pharmaceutical compositionsin which said compound is the active agent, and their medicinal use inhumans and animals as coronary active agents, particularly for theircoronary vessel dilating effect and their antihypertensive effect.

It has already been disclosed that 1,4-dihydropyridines possessinteresting pharmacological properties (F. Bossert and W. Vater, "DieNaturwissenschaften" 1971, 58th year, Issue 11, page 578).

The present invention comprises 1,4-dihydropyridine carboxylic acidesters of the formula: ##STR2## or pharmaceutically acceptable, nontoxicsalts thereof wherein R is hydrogen, straight- or branched-chain loweralkyl, lower alkenyl preferable of 2 to 4 carbon atoms or lower alkinylpreferable of 2 to 4 carbon atoms;

R¹ and R⁴ are the same or different and are each hydrogen or straight-or branched-chain lower alkyl;

X is straight- or branched-chain lower alkylene;

Y is α-, β- or γ-pyridyl, or the moiety NR'R" wherein

R' and R" are the same or different and are each hydrogen or loweralkyl, or

R' and R", together with the nitrogen atom to which they are attached,form a 5-, 6- or 7-membered heterocyclic ring wherein said nitrogen atomis the only heteroatom, or a 5-, 6- or 7-membered heterocyclic ringwhich has at least one additional heteroatom selected from the groupconsisting of oxygen, sulphur, NH or N-(lower alkyl);

R² is aryl unsubstituted or substituted by 1, 2 or 3 substituentsselected from the group consisting of nitro, cyano, azido, lower alkyl,lower alkoxy, lower acyloxy, carb-(lower alkoxy), amino, loweracylamino, lower alkylamino, di-(lower alkylamino), SO_(n) -(loweralkyl) wherein n is 0, 1 or 2, phenyl, trifluoromethyl and halogen;benzyl; phenyl-ethyl styryl; cycloalkyl; cycloalkenyl; or naphthyl,quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyrryl, furyl or thenylunsubstituted or substituted by one or more substituents selected fromthe group consisting of lower alkyl, lower alkoxy, nitro and halogen;and

R³ is a straight- or branched-chain lower hydrocarbon unsubstituted orsubstituted by one or two hydroxyl groups, a straight- or branched-chainlower hydrocarbon interrupted by one or two oxygen atoms, the moiety--OQ wherein Q is straight, branched or cyclic, saturated, partiallyunsaturated or unsaturated lower hydrocarbon unsubstituted orsubstituted by one or two hydroxyl groups, a straight, branched orcyclic, saturated, partially unsaturated or unsaturated lowerhydrocarbon interrupted by one or two oxygen atoms or the moietyO--X'--Y' wherein

X' is straight- or branched-chain lower alkylene and

Y' is α-, β- or γ-pyridyl, or the moiety NR'R" wherein

R' and R" are the same or different and are each hydrogen or lower alkylor

R' and R" together with the nitrogen atom to which they are attachedform a 5-, 6- or 7-membered heterocyclic ring wherein said nitrogen atomis the only heteroatom or a 5-, 6- or 7-membered heterocyclic ring whichhas at least one additional heteroatom selected from the groupconsisting of oxygen, sulphur, NH or N-(lower alkyl).

In addition to their coronary vessel dilating effect andantihypertensive effect, the compounds of the present invention are alsouseful for their antifibrillation action, vascular spasmolytic action,muscular spasmolytic action and for their action on the cholesterollever and lipid level of the blood.

According to one embodiment of the present invention

R is hydrogen, straight- or branched-chain alkyl of 1 to 4 carbon atomsor straight- or branched-chain alkenyl of 2 to 4 carbon atoms;

R¹ and R⁴ are the same or different and are each hydrogen or straight-or branched-chain alkyl of 1 to 4 carbon atoms;

X is straight- or branched-chain alkylene of 1 to 4 carbon atoms;

Y is α-, β- or γ-pyridyl, or the moiety NR'R" wherein

R' and R" are the same or different and are each hydrogen or alkyl of 1to 4 carbon atoms, or

R' and R" together with the nitrogen atom to which they are attachedform a 5-, 6-, or 7-membered heterocyclic ring wherein said nitrogenatom is the only heteroatom, or a 5-, 6- or 7-membered heterocyclic ringwhich has at least one additional heteroatom selected from the groupconsisting of oxygen, sulphur, NH or N-(lower alkyl);

R² is phenyl unsubstituted or substituted by 1 or 2 nitro, cyano, azido,alkyl of 1 to 4 carbon atoms, acetoxy, amino, acetylamino, alkylamino of1 to 4 carbon atoms, dialkylamino of 1 to 4 carbon atoms in each alkylmoiety, chloro, bromo, or trifluoromethyl groups, or by a carb-(loweralkoxy) group or a moiety of the formula SO_(n) -alkyl wherein n is 0 or2 and the alkyl moiety has 1 to 4 carbon atoms, or by 1 to 3 alkoxygroups of 1 to 4 carbon atoms; benzyl; phenyl-ethyl styryl; cycloalkylof 5 or 6 carbon atoms; cycloalkenyl of 5 or 6 carbon atoms; ornaphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyrryl, furyl orthenyl unsubstituted or substituted by alkyl of 1 to 4 carbon atoms,alkoxy of 1 to 4 carbon atoms, nitro, chloro, or bromo; and

R³ is the moiety --OQ wherein Q is straight- or branched-chain alkyl of1 to 4 carbon atoms, or alkoxyalkyl of up to 6 carbon atoms in bothmoieties, or the moiety --O--X'--Y' wherein

X' is straight- or branched-chain alkylene of 1 to 4 carbon atoms, and

Y' is α-, β- or γ-pyridyl, or the moiety NR'R" wherein

R' and R" are the same or different and are each hydrogen or alkyl of 1to 4 carbon atoms, or

R' and R" together with the nitrogen atom to which they are attachedform a 5-, 6- or 7-membered heterocyclic ring wherein said nitrogen atomis the only heteroatom, or a 5-, 6- or 7-membered heterocyclic ringwhich has at least one additional heteroatom selected from the groupconsisting of oxygen, sulphur, NH or N-(lower alkyl).

It is preferred that the alkyl moiety of R has 1 to 3 carbon atoms andof R¹ and R⁴ has one or two carbon atoms.

According to another embodiment of the present invention

R² is phenyl unsubstituted or substituted by azido or SO_(n) -alkylwherein n is 0 or 2 and alkyl is of 1 to 4 carbon atoms, or by 1 or 2amino moieties, alkyl-amino moieties of 1 or 2 carbon atoms, 1 or 2acetylamino moieties, 1 or 2 acetoxy moieties, 1 or 2 alkyl moieties of1 or 2 carbon atoms, 1 to 3 alkoxy moieties of 1 or 2 carbon atoms or 1or 2 members selected from the group consisting of nitro, cyano, chloro,bromo and trifluoromethyl; benzyl; phenyl-ethyl styryl; cycloalkyl of 5or 6 carbon atoms; cycloalkenyl of 5 or 6 carbon atoms; or naphthyl,quinolyl, isoquinolyl, pyridyl, pyrimidyl, pyrryl, furyl or thenylunsubstituted or substituted by alkyl of 1 or 2 carbon atoms, alkoxy of1 or 2 carbon atoms, nitro, chloro or bromo; and

R³ is the moiety --OQ wherein

Q is straight- or branched-chain alkyl of 1 to 4 carbon atomsinterrupted by 1 oxygen atom or the moiety --O--X'--Y' wherein

X' is straight- or branched-chain alkylene of 1 to 4 carbon atoms, and

Y' is α, β- or γ-pyridyl, or the moiety NR'R" wherein

R' and R" are the same or different and are each hydrogen or alkyl of 1to 4 carbon atoms, or

R' and R" together with the nitrogen atom to which they are attachedform a 5-, 6- or 7-membered heterocyclic ring wherein said nitrogen atomis the only heteroatom, or a 5-, 6- or 7-membered heterocyclic ringwhich has at least one additional heteroatom selected from the groupconsisting of oxygen, sulphur, NH or N-(lower alkyl).

According to another embodiment of the present invention

R is hydrogen or straight- or branched-chain alkyl of 1 to 4 carbonatoms,

R¹ and R⁴ are the same or different and are each straight- orbranched-chain alkyl of 1 to 4 carbon atoms,

X is straight- or branched-chain alkylene of 1 to 4 carbon atoms,

Y is α-, β- or γ-pyridyl, dimethylamino, diethylamino, morpholine,thiomorpholine, pyrrolidine or methylpiperazine.

R² is phenyl; phenyl substituted by 1 or 2 substituents selected fromthe group consisting of nitro, cyano, azido, carbethoxy, acetylamino,dimethylamino, SO_(n) -alkyl wherein n is 0, 1 or 2 and the alkyl moietyhas 1 or 2 carbon atoms, chloro and trifluoromethyl, or by 1 to 3methoxy groups; styryl; naphthyl; quinolyl; pyridyl; nitropyridyl;pyrimidyl; dimethoxypyrimidyl; furyl; bromofuryl; thenyl; ornitrothenyl; and

R³ is the moiety -OQ wherein

Q is straight- or branched-chain alkyl of 1 to 4 carbon atoms,methoxyethyl or the moiety --O--X'--Y' wherein

X' is straight- or branched-chain alkylene of 1 to 4 carbon atoms, and

Y' is α-, β- or γ-pyridyl, morpholine, methylpyrrolidine ormethylpiperazine.

According to another embodiment of the present invention

R is hydrogen or straight- or branched-chain alkyl of 1 to 4 carbonatoms,

R¹ is straight- or branched-chain alkyl of 1 to 3 carbon atoms,

R⁴ is straight- or branched-chain alkyl of 1 to 4 carbon atoms,

X is straight- or branched-chain alkylene of 1 to 3 carbon atoms,

Y is α-, β- or γ-pyridyl, dimethylamino, diethylamino, pyrrolidine,morpholine, thiomorpholine, or methylpiperazine,

R² is phenyl; phenyl substituted by nitro, nitro and thiomethyl, nitroand trifluoromethyl, nitro and chloro, dinitro, trifluoromethyl,di-trifluoromethyl, chloro, dichloro, cyano, mercapto, methylsulphinyl,ethylsulphonyl, azido, dimethylamino, methoxy, methoxy and fluoro,trimethoxy, fluoro, carbethoxy or acetamino; styryl; naphthyl; pyridyl;nitropyridyl; pyrimidyl; dimethoxypyrimidyl; bromofuryl; nitrothenyl; orquinolyl; and

R³ is straight- or branched-chain alkoxy of 1 to 4 carbon atoms,methoxyethoxy, pyridylethoxy, morpholinoethoxy, morpholinoisopropoxy,methylpiperozinopropoxy, or ethylpyrrolidine.

The term lower alkyl denotes a univalent saturated branched or straighthydrocarbon chain containing from 1 to 6 carbon atoms. Representative ofsuch lower alkyl groups are thus methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec. butyl, tert. butyl, pentyl, isopentyl, neopentyl,tert. pentyl, hexyl and the like.

The term lower alkenyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalethylenic unsaturation as, for example, vinyl, allyl, isopropenyl,2-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl,4-hexenyl, and the like.

The term lower alkinyl denotes a univalent branched or straighthydrocarbon chain containing from 2 to 6 carbon atoms and nonterminalacetylenic unsaturation as, for example, ethynyl, 2-propynyl,4-pentynyl, and the like.

The term lower alkoxy denotes a straight or branched hydrocarbon chainbound to the remainder of the molecule through an ethereal oxygen atomas, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, pentoxy and hexoxy.

The term halogen denotes the substituents fluoro, chloro, bromo andiodo.

As indicated, the present invention also pertains to thepharmaceutically acceptable nontoxic salts of these basic compounds.Such salts include those derived from organic and inorganic acids suchas, without limitation, hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, methane sulphonic acid, acetic acid, tartaric acid,lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbicacid, aconitic acid, salicyclic acid, phthalic acid, embonic acid,enanthic acid, and the like.

The compounds of the present invention may be produced by the followingprocesses:

a. an acyl-fatty acid ester of the formula:

    R.sup.1 --CO--CH.sub.2 --COO--X--Y                         (II)

is reacted with ammonia or with an amine of the formula:

    H.sub.2 --R                                                (III)

or a salt thereof, to produce an enamine of the formula: ##STR3## whichis then reacted with or without intermediate isolation, with a ylidenederivative of the formula: ##STR4## to produce the desired compound; or

b. a β-dicarbonyl compound of the formula:

    R.sup.4 --CO--CH.sub.2 --CO--R.sup.3                       (VI)

is reacted with ammonia or an amine of the formula:

    H.sub.2 N--R                                               (III)

or a salt thereof, to produce an enamine of the formula: ##STR5## whichis then reacted with or without intermediate isolation with a ylidenederivative of the formula: ##STR6## to produce the desired compound; or

b. a β-dicarbonyl compound of the formula:

    R.sup.4 --CO--CH.sub.2 --CO--R.sup.3                       (VI)

and an enamine of the formula: ##STR7## are reacted with an aldehyde ofthe formula:

    R.sup.2 --CHO                                              (IX)

to produce the desired compound; or

d. an acyl-fatty acid ester of the formula:

    R.sup.1 --CO--CH.sub.2 --COO--X--Y                         (II)

and an enamine of the formula: ##STR8## are reacted with an aldehyde ofthe formula:

    R.sup.2 --CHO                                              (IX)

to produce the desired compound; or

e. two moles of an acyl-fatty acid ester of the formula:

    R.sup.1 --CO--CH.sub.2 --COO--X--Y                         (II)

and one mole of ammonia or an amine of the formula:

H₂ N--R (III)

or a salt thereof, are reacted with an aldehyde of the formula:

R² --CHO (IX)

to produce the desired compound; or

f. a 1,4-dihydropyridine derivative of the formula: ##STR9## wherein Zis hydrogen or an alkali metal or alkaline earth metal cation is reactedwith a compound of the formula

    Hal--X--Y                                                  (XI)

wherein

Hal is chlorine or bromine to produce the desired compound.

In the above formulae II to XI, R, R¹, R², R³, R⁴, X and Y are all asdefined above.

Throughout this specification the different reactions (a) to (f) will bereferred to respectively as Process Variants (a) to (f).

In Process Variants (a), (b), and (e), the amine of formula III will beammonia when a compound in which R is a hydrogen atom is being prepared.

Surprisingly, the compounds of the present invention exhibit, for thesame strength of effect, a considerably better solubility than known1,4-dihydropyridines.

If 3'-nitrobenzylideneacetoacetic acid methyl ester, acetoacetic acid(α-pyridyl)-methyl ester and methylamine are used as starting materials,with N-methylaminocrotonic acid (α-pyridyl)-methyl ester as theintermediate enamine, which need not be isolated, the course of thereaction for Process Variant (a) can be represented as follows:##STR10##

If 3'-nitrobenzylidenacetoacetic acid (α-pyridyl)-methyl ester,acetoacetic acid methol ester and methylamine are used as the startingmaterials, with N-methylaminocrotonic acid methyl ester as theoptionally isolated intermediate enamine, the course of the reaction forProcess Variant (b) is as follows: ##STR11##

If 2-nitrobenzaldehyde, acetoacetic acid methyl ester and aminocrotonicacid (β-pyridyl)-methyl ester are used as starting materials, the courseof the reaction of Process Variant (c) takes place according to thefollowing equation: ##STR12##

If 2-nitrobenzaldehyde, aminocrotonic acid methyl ester and acetoaceticacid (β-pyridyl)-methyl ester are used as starting materials, the courseof the reaction for Process Variant (d) can be represented as follows:##STR13##

If 2-trifluoromethylbenzaldehyde, acetoacetic acid(β-N-morpholine)-ethyl ester and ammonia are used as starting materials,aminocrotonic acid (β-N-morpholine)-ethyl ester being the intermediateenamine, the course of the reaction for Process Variant (e) is asfollows: ##STR14##

If a 1,4-dihydropyridine-monocarboxylic acid is used as startingmaterial, the reaction for Process Variant (f) is as follows: ##STR15##

The 1,4-dihydropyridine-monocarboxylic acids used as starting materialsin Process Variant (f) can be prepared by alkaline saponfication of the1,4-dihydropyridine 3,5-dicarboxylic acid diesters.

A. In the compounds of the invention and in the basically-substitutedβ-ketocarboxylic acid esters of the formula:

    R.sup.1 --CO--CH.sub.2 COO--X--Y                           (II)

r¹ is preferably hydrogen or straight- or branched-chain alkyl of 1 to 4carbon atoms, especially alkyl of 1 or 2 carbon atoms;

X is preferably straight- or branched-chain alkylene of 1 to 4 carbonatoms; and

Y is preferably α-, β- or γ-pyridyl or NR'R" wherein R' and R" are eachhydrogen or straight- or branched-chain alkyl of 1 to 4 carbon atoms, orR' and R", together with the nitrogen atom to which they are attachedform a 5-, 6- or 7-membered heterocyclic ring wherein said nitrogen isthe only heteroatom or the ring contains oxygen, sulfur, NH or N-(loweralkyl) as an additional ring member.

The basic-substituted β-ketocarboxylic acid esters of the formula IIused as starting materials in Proccess Variants (a) and (b) according tothe invention were not previously known but can be produced according toknown processes, for example, from diketene and basic-substitutedalcohols (Chemical Abstracts 50, 16668 h (1956)).

As examples of these esters there may be mentioned:

Basic-substituted β-ketocarboxylic acid esters

Acetoacetic acid (α-pyridyl)-methyl ester,

acetoacetic acid (β-pyridyl)-methyl ester,

acetoacetic acid (γ-pyridyl)-methyl ester,

acetoacetic acid (β-N-morpholine)-ethyl ester,

acetoacetic acid (N-morpholine)-isopropyl ester,

acetoacetic acid (β-N-piperidine)-ethyl ester,

acetoacetic acid (β-N-piperidine)-isopropyl ester,

acetoacetic acid (β-N-thiomorpholine)-ethyl ester,

acetoacetic acid (β-N-thiomorpholine)-isopropyl ester,

acetoacetic acid (β-N-pyrrolidine)-ethyl ester,

acetoacetic acid (β-N,N'-methylpiperazine)-ethyl ester,

propionylacetic acid (α-pyridyl)-methyl ester,

propionylacetic acid (β-N-morpholine)-ethyl ester,

butyrylacetic acid (β-pyridyl)-methyl ester,

isobutyrylacetic acid (γ-pyridyl)-methyl ester,

acetoacetic acid (β-diethylamino)-ethyl ester and

acetoacetic acid (γ-dimethylamino)-propyl ester.

In the compounds of the invention, and in the amines of the formula:

    H.sub.2 N--R                                               (III)

used as starting materials in Process Variants (a), (b) and (e), R ispreferably hydrogen or straight- or branched-chain alkyl of 1 to 4carbon atoms or alkenyl of 2 to 4 carbon atoms, especially alkyl of 1 to3 carbon atoms.

The amines of formula III used according to the invention are alreadyknown.

As examples of these amines there may be mentioned:

Amines:

Ammonia,

methylamine,

propylamine,

isopropylamine,

butylamine,

isobutylamine and

allylamine.

In the enaminocarboxylic acid esters of the formula: ##STR16##

R, R¹, X and Y are preferably as above defined for formulae II and III.

The enaminocarboxylic esters used as intermediates in Process Variants(a) and (c) according to the invention are not previously known but canbe produced according to known methods (A. C. Cope, J. A. C. S. 67, 1017(1945)) from appropriate basic-substituted β-ketocarboxylic acid esters.

As examples of these enaminocarboxylic acid esters there may bementioned:

Basically-substituted enaminocarboxylic acid esters

β-Aminocrotonic acid (β-N-morpholine)-ethyl ester,

β-aminocrotonic acid (γ-pyridyl)-methyl ester,

β-N-methyl-aminoccrotonic acid (α-pyridyl)-methyl ester,

β-N-ethylaminocrotonic acid (N,N'-methylpiperazine)-isopropyl ester and

β-N-allylaminocrotonic acid (N-thiomorpholine)-propyl ester.

In the compounds according to the invention, and in the ylidenederivatives of the formula: ##STR17## which are used as startingmaterials in Process Variant (a): R² is preferably phenyl unsubstitutedor substituted by 1 or 2 nitro groups, especially by one nitro group, byone cyano group, by one azido group, by 1 or 2 trifluoromethyl groups,especially by one trifluoromethyl group, by one SO_(n) -alkyl groupwherein n is 0 or 2 and the alkyl moiety has 1 to 4 carbon atoms, by 1or 2 alkyl groups, by 1 to 3 alkoxy groups, by 1 or 2 acetoxy, amino,acetylamino, alkylamino or dialkylamino groups, each alkyl or alkoxymoiety having 1 to 4, especially 1 or 2, carbon atoms, or by 1 or 2chlorine or bromine atoms, with the total number of the substituentsbeing at most 3; or R² is benzyl, styryl, cycloalkyl of 5 or 6 carbonatoms or cycloalkenyl of 5 or 6 carbon atoms; or R² is pyridyl,pyrimidyl, naphthyl, quinolyl, isoquinolyl, thenyl, pyrryl or furylunsubstituted or substituted by alkyl or alkoxy of 1 to 4 carbon atoms,especially of 1 or 2 carbon atoms, by nitro or by halogen, especiallychlorine or bromine,

R³ is preferably a straight- or branched-chain hydrocarbon of 1 to 4carbon atoms unsubstituted or substituted by hydroxyl or interrupted byoxygen; or R³ is the moiety --OQ wherein Q is a straight, branched orcyclic, saturated, partially unsaturated or unsaturated hydrocarbon of 1to 6 carbon atoms unsubstituted or substituted by hydroxyl or by oxygen;or R³ is the moiety --O--X'--Y' wherein

X' is straight- or branched-chain alkylene or 1 to 4 carbon atoms, and

Y' is α-, β- or γ-pyridyl, or the moiety NR'R" wherein R' and R" are thesame or different and are each hydrogen or alkyl of 1 to 4 carbon atoms,or R' and R" together with the nitrogen atom to which they are attachedform a 5-, 6- or 7-membered heterocyclic ring wherein said nitrogen atomis the only heteroatom, or a 5-, 6- or 7-membered heterocyclic ringwhich has at least one additional heteroatom selected from the groupconsisting of oxygen, sulphur, NH or N-(lower alkyl); and

R⁴ is preferably hydrogen or straight- or branchedchain alkyl of 1 to 4carbon atoms, especially of 1 or 2 carbon atoms.

The ylidene-β-ketocarboxylic acid esters of the formula V which are usedaccording to the invention are already known or can be producedaccording to known methods (Org. Reactions, XV, 204 FF, (1967)).

As examples, there may be mentioned:

Ylidene-β-ketocarboxylic acid esters:

Benzylideneacetoacetic acid methyl ester,

2'-nitrobenzylideneacetoacetic acid methyl ester,

2'-nitrobenzylideneacetylacetone,

benzylideneacetylacetone,

3'-nitrobenzylideneacetoacetic acid methyl ester,

3'-nitrobenzylideneacetoacetic acid propargyl ester,

3'-nitrobenzylideneacetoacetic acid allyl ester,

3'-nitrobenzylideneacetoacetic acid β-methoxyethyl ester,

3'-nitrobenzylideneacetoacetic acid β-ethoxyethyl ester,

3'-nitrobenzylideneacetoacetic acid isopropyl ester,

3'-nitrobenzylideneacetylacetone,

4'-nitrobenzylideneacetylacetone,

4'-nitrobenzylideneacetoacetic acid β-propoxyethyl ester,

4'-nitrobenzylideneacetoacetic acid n-propyl ester,

3'-nitro-6'-chlorobenzylideneacetoacetic acid methyl ester,

2'-cyanobenzylideneacetoacetic acid methyl ester,

2'-cyanobenzylideneacetoacetic acid ethyl ester,

2'-cyanobenzylidenepropionylacetic acid ethyl ester,

3'-cyanobenzylideneacetoacetic acid methyl ester,

3'-nitro-4'-chlorobenzylideneacetylacetone,

3'-nitro-4'-chlorobenzylideneacetoacetic acid t-butyl ester,

3'-nitro-4'-chlorobenzylideneacetoacetic acid methyl ester,

2'-nitro-4-methoxybenzylideneacetoacetic acid methyl ester,

2'-cyano-4'-methylbenzylideneacetoacetic acid ethyl ester,

2'-azidobenzylideneacetoacetic acid ethyl ester,

3'-azidobenzylideneacetylacetone,

2'-methylmercaptobenzylideneacetoacetic acid methyl ester,

2'-methylmercaptobenzylideneacetoacetic acid isopropyl ester,

2'-sulphinylmethylbenzylideneacetoacetic acid ethyl ester,

2'-sulphonylmethylacetoacetic acid allyl ester,

4-sulphonylmethylacetoacetic acid ethyl ester,

(1'-naphthylidene)-acetoacetic acid methyl ester,

(1'-naphthylidene)-acetoacetic acid ethyl ester,

(2'-naphthylidene)-acetoacetic acid ethyl ester,

(2'-ethoxy-1'-naphthylidene)-acetoacetic acid methyl ester,

(2'-methoxy-1'-naphthylidene)-acetoacetic acid ethyl ester,

5'-bromo-(1'-naphthylidene)-acetoacetic acid methyl ester,

(2'quinolyl)-methylideneacetoacetic acid ethyl ester,

(3'-quinolyl)-methylideneacetoacetic acid methyl ester,

(4'-quinolyl)-methylideneacetoacetic acid ethyl ester,

(8'-quinolyl)-methylideneacetoacetic acid ethyl ester,

(1'-isoquinolyl)-methylideneacetoacetic acid methyl ester,

(3'-isoquinolyl)-methylideneacetoacetic acid methyl ester,

α-pyridylmethylideneacetoacetic acid methyl ester,

α-pyridylmethylideneacetoacetic acid ethyl ester,

α-pyridylmethylideneacetoacetic acid allyl ester,

α-pyridylmethylideneacetoacetic acid cyclohexyl ester,

β-pyridylmethylideneacetoacetic acid β-methoxyethyl ester,

γ-pyridylmethylideneacetoacetic acid methyl ester,

6-methyl-α-pyridylmethylideneacetoacetic acid ethyl ester,

4',6'-dimethoxy-(5'-pyrimidyl)-methylideneacetoacetic acid ethyl ester,

(2'-thenyl)-methylideneacetoacetic acid ethyl ester,

(2'-furyl)-methylideneacetoacetic acid allyl ester,

(2'-pyrryl)-methylideneacetoacetic acid methyl ester,

3'-nitro-benzylidenepropionylacetic acid ethyl ester,

α-pyridylmethylidenepropionylacetic acid methyl ester,

α-pyridylmethylideneacetylacetone,

2'-, 3'- and 4'-methoxybenzylideneacetoacetic acid ethyl ester,

2'-, 3'- and 4'-methoxybenzylideneacetylacetone,

2'-methoxybenzylideneacetoacetic acid allyl ester,

2'-methoxybenzylideneacetoacetic acid propargyl ester,

2'-methoxybenzylidene-β-methoxyethyl ester,

2'-isopropoxybenzylideneacetoacetic acid ethyl ester,

3'-butoxybenzylideneacetoacetic acid methyl ester,

3',4',5'-trimethoxybenzylideneacetoacetic acid allyl ester,

2'-methylbenzylidenepropionylacetic acid methyl ester,

2'-, 3'- and 4'-methylbenzylideneacetoacetic acid ethyl ester,

2'-methylbenzylideneacetoacetic acid β-methoxyethyl ester,

2'-methylbenzylideneacetoacetic acid β-propoxyethyl ester,

2'-methylbenzylideneacetylacetone,

3',4'-dimethoxy-5'-bromobenzylideneacetoacetic acid ethyl ester,

2'-, 3'- and 4'-chloro/bromo/fluorobenzylideneacetoacetic acid ethylester,

2'-fluorobenzylideneacetoacetic acid methyl ester,

3'-chlorobenzylideneacetylacetone,

3'-chlorobenzylidenepropionylacetic acid ethyl ester,

3'-chlorobenzylideneacetoacetic acid ethyl ester,

2'-chlorobenzylideneacetoacetic acid allyl ester,

2'-, 3'- and 4'-trifluoromethylbenzylideneacetoacetic acid propylesters,

2'-trifluoromethylbenzylideneacetoacetic acid isopropyl ester,

3'-trifluoromethylbenzylideneacetoacetic acid methyl ester,

2'-carboethoxybenzylideneacetoacetic acid ethyl ester,

3'-carboxymethylbenzylideneacetoacetic acid methyl ester,

4-carboxyisopropylbenzylideneacetoacetic acid isopropyl ester, and

4'-carboxymethylbenzylideneacetoacetic acid allyl ester.

B. in the β-dicarbonyl compounds of the formula:

    R.sup.4 --CO--CH.sub.2 --CO--R.sup.3                       (VI)

used as starting materials in Process Variants (b) and (c), R³ and R⁴preferably have the preferred meanings set forth above with respect toformula V.

The β-dicarbonyl compounds of the formula VI employed according to theinvention are already known or can be produced by known processes (Pohl,Schmidt, U.S. Pat. No. 2,351,366 (1940), ref. in C.A. 1944, 5224).

Apart from the compounds already listed above, the following may bementioned as examples: β-Dicarbonyl Compounds:

Formylacetic acid ethyl ester,

acetoacetic acid methyl ester,

acetoacetic acid ethyl ester,

acetoacetic acid propyl ester,

acetoacetic acid isopropyl ester,

acetoacetic acid butyl ester,

acetoacetic acid (α- and β-)-methoxyethyl esters,

acetoacetic acid (α- and β-)-propoxyethyl esters,

acetoacetic acid (α- and β-)-hydroxyethyl esters,

acetoacetic acid allyl ester,

acetoacetic acid propargyl ester,

propionylacetic acid ethyl ester,

butyrylacetic acid methyl ester,

isobutyrylacetic acid ethyl ester,

acetoacetic acid furfuryl ester,

acetone-acid tetrahydrofurfuryl ester,

2,4-pentadione,

3,5-heptadione,

4,6-nonanedione, and

2,6-dimethyl-3,5-heptadione.

In the β-enaminocarbonyl compounds, used as starting materials inProcess Variants (b) and (d), of the formula: ##STR18## R, R³ and R⁴ arepreferably as above defined for formulae IV and V.

The β-enamino-carbonyl compounds of the formula VII employed accordingto the invention are already known or can be produced by known processes(A. C. Cope, J.A.C.S. 67, 1017 (1945)).

As examples there may be mentioned:

Enamino-keto compounds

β-Aminocrotonic acid methyl ester,

β-aminocrotonic acid ethyl ester,

β-aminocrotonic acid isopropyl ester,

β-aminocrotonic acid ethyl ester,

β-aminocrotonic acid β-methoxyethyl ester,

β-aminocrotonic acid cyclohexyl ester,

β-N-methylaminocrotonic acid methyl ester,

β-N-methylaminocrotonic acid ethyl ester,

β-N-methylaminocrotonic acid isopropyl ester,

β-N-ethylaminocrotonic acid ethyl ester,

β-N-isopropylaminocrotonic acid methyl ester,

β-N-methylaminocrotonic acid β-methoxyethyl ester,

1-amino-buten-1-en-3-one,

2-amino-penten-2-en-4-one and

2-methylamino-penten-2-en-4-one.

In the ylidene-β-keto compounds used according to the invention asstarting materials in Process Variant (b), of the formula: ##STR19## R¹,R², X and Y preferably are as above defined for formulae II and V.

The ylidene derivative of the formula VIII employed according to theinvention are either known or can be produced by known methods (Org.Reactions XV, 204 ff, (1967)).

Apart from the compounds already listed above, the following may bementioned as examples:

Ylidene-β-keto compounds

Benzylidene-acetoacetic acid (α-pyridyl)-methyl ester,

2'-nitrobenzylideneacetoacetic acid (β-N-morpholine)ethyl ester,

2-trifluoromethylbenzylidene-acetoacetic acid(γ-N,N-methylpiperazine)-propyl ester,

2'-cyanobenzylideneacetoacetic acid (β-diethylamino)-ethyl ester,

α-pyridylmethylidenepropionylacetic acid (β-pyridyl)-methyl ester,

3'-chlorobenzylideneacetoacetic acid (β-N-thiomorpholine)ethyl ester,

2'-sulphonylmethylbenzylideneacetoacetic acid (γ-pyridyl)methyl ester,

(1'-naphthylidene)-acetoacetic acid (α-pyridyl)-methyl ester and

(8'-quinolylmethylideneacetoacetic acid (α-pyridyl)-methyl ester.

C. The aldehydes of the formula (IX) which can be used according to theinvention as starting materials in Process Variant IX are already knownor can be produced according to known methods (E. Mosettig, Org.Reactions, VIII, 218 ff. (1954)).

As examples there may be mentioned:

Aldehydes

Benzaldehyde,

2-, 3- and 4-methoxybenzaldehydes,

2-isopropoxybenzaldehyde,

3-butoxybenzaldehyde, 3,4-dihydroxymethylenebenzaldehyde,

3,4,5-trimethoxybenzaldehyde,

2-, 3- and 4-chloro/bromo/fluorobenzaldehyde,

2,4- and 2,6-dichlorobenzaldehyde,

2,4-dimethylbenzaldehyde,

3,5-diisopropyl-4-methoxybenzaldehyde,

2-, 3- and 4-nitrobenzaldehyde,

2,4- and 2,6-dinitrobenzaldehyde,

2-nitro-6-bromobenzaldehyde,

2-nitro-3-methoxy-6-chlorobenzaldehyde,

2-nitro-4-chlorobenzaldehyde,

2-nitro-4-methoxybenzaldehyde,

2-, 3- and 4-trifluoromethylbenzaldehyde,

2-, 3- and 4-dimethylaminobenzaldehyde,

4-dibutylaminobenzaldehyde,

4-acetaminobenzaldehyde,

2-, 3- and 4-cyanobenzaldehyde,

2-nitro-4-cyanobenzaldehyde,

3-chloro-4-cyanobenzaldehyde,

2-, 3- and 4-methylmercaptobenzaldehyde,

2-methylmercapto-5-nitrobenzaldehyde,

2-butylmercaptobenzaldehyde,

2-, 3- and 4-methylsulphinylbenzaldehyde,

2-, 3- and 4-methylsulphonylbenzaldehyde,

benzaldehyde-2-carboxylic acid ethyl ester,

benzaldehyde-3-carboxylic acid isopropyl ester,

benzaldehyde-4-carboxylic acid butyl ester,

3-nitrobenzaldehyde-4-carboxylic acid ethyl ester,

cinnamaldehyde,

hydrocinnamaldehyde,

formylcyclohexane,

1-formylcyclohex-3-ene,

1-formylcyclohex-1,3-ine,

1-formylcyclopent-3-ene,

α-, β- and γ-pyridinaldehydes,

6-methylpyridine-2-aldehyde,

furan-2-aldehyde,

thiophen-2-aldehyde,

pyrrol-2-aldehyde,

2-, 3- and 4-azidobenzaldehydes,

pyrimidin-4-aldehyde,

5-nitro-6-methylpyridin-2-aldehyde,

1- and 2-naphthaldehyde,

5-bromo-1-naphthaldehyde,

quinolin-2-aldehyde,

7-methoxy-quinolin-4-aldehyde and

isoquinolin-1-aldehyde.

The 1,4-dihydropyridinemonocarboxylic acid employed as startingmaterials in Process Variant (f) according to the invention, of theformula: ##STR20## wherein R, R¹, R², R³, R⁴ and Z preferably have thepreferred meanings set forth above, are as yet unknown and can beproduced by alkaline hydrolysis of 1,4-dihydropyridine3,5-dicarboxylicacid diesters.

As examples there may be mentioned:

1,4-Dihydropyridine-monocarboxylic acids

2,6-Dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid ethyl ester,

2,6-dimethyl-4-(3'-trifluoromethylphenyl)-1,4-dihydropyridine3-carboxylicacid methyl ester,

2,6-dimethyl-4-(3'-chlorophenyl)-dihydropyridine-3-carboxylicacid-5-carboxylic acid isopropyl ester,

1,2,6-trimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid methyl ester,

1,2,6-trimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid-5-carboxylic acid furfuryl ester,

1,2,6-trimethyl-4-(2'-chlorophenyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid propargyl ester,

1-methyl-2,6-diethyl-4-(2'-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid ethyl ester,

1,2,6-trimethyl-4-(1'-naphthyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid methyl ester,

1,2,6-triethyl-4-(4'-methylmercaptophenyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid butyl ester,

1,2,6-trimethyl-4-(α-pyridyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid methyl ester and

1,2,6-trimethyl-4-(4'-quinolyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid ethyl ester.

In all the Process Variants, water or any inert organic solvent can beused as diluent. Preferred diluents are alcohols (such as ethanol,methanol, and isopropanol), ethers (such as dioxane and diethyl ether),glacial acetic acid, dimethylformamide, dimethylsulphoxide, acetonitrileand pyridine.

The reaction temperatures can be varied over a substantial range. Ingeneral, the reaction is carried out at between 20° C and 150° C,preferably at the boiling point of the solvent.

The reactions can be carried out under normal pressure, but also atelevated pressure. In general, they are carried out under normalpressure.

In carrying out the processes according to the present invention, thesubstances participating in the reaction are generally employedapproximately in molar amounts except where stated, and except for theamine or its salt which when used is appropriately added in an excess of1 or 2 mols.

The following may be mentioned as representative important compoundsaccording to the present invention:

2,6-Dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3- (γ-dimethylamino)-propyl ester 5-methyl ester.

2,6-Dimethyl-4-(2'-methylsulphinylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(N,N'-methylpiperazino)ethyl ester 5-butyl ester.

2,6-Diethyl-4-(2'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester.

2-Methyl-6-ethyl-4-(3'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-N-morpholino)-propyl ester 5-isopropyl ester.

2,6-Isopropyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(β-pyridyl)-methyl ester 5-ethyl ester.

1,2,6-Trimethyl-4-(2'-4'-dinitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-pyridyl)-methyl ester 5-methyl ester.

1-Methyl-2,6-diethyl-4-(2'-4'-ditrifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-pyridyl)-methyl ester.

1,2,6-Triethyl-4-(3'-nitro-6'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(β-thiomorpholino)-ethyl ester 5-ethyl ester.

1-Isopropyl-2,6-diethyl-4-(3'-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-N-pyrrolidino)-ethyl ester.

1-Butyl-2,6-dimethyl-4-(3'-4'-5'-trimethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-[2'-(2'-(α-pyridyl)-ethyl ester] 5-ethyl ester.

2,6-Dimethyl-4-(2'-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-N,N'-methylpiperazino)-propyl ester 5-methyl ester.

2,6-Diethyl-4-(4'-carbethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(α-pyridyl)-methyl ester 1,5-tert.butyl ester.

2,6-Dimethyl-4-(5'-nitro-α-pyridyl)-1,4-dihydrolpyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-ethyl ester.

2,6-Diethyl-4-(4'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(β-N-morpholino)-ethyl ester 5-ethyl ester.

The compounds of the present invention are readily water-soluble in theform of salts (formed from acids) and do not require any solubilizingagent.

As noted above, the compounds of the present invention demonstrate theability to reduce blood pressure and to effect a dilation of thecoronary vessels. They can accordingly by used where either or both ofthese effects are desired. Thus upon parenteral, oral or sublingualadministration, the compounds produce a distinct and long lastingdilating of the coronary vessels which is intensified by a simultaneousnitrite-like effect of reducing the load on the heart. The effect onheart metabolism is thus one of energy saving. In addition, thecompounds lower the blood pressure of normotonic and hypertonic animalsand can thus be used as antihypertensive agents.

In addition to the effect on blood pressure and coronary vessels, thecompounds also lower the excitability of the stimulus formation andexcitation conduction system within the heart so that anantifibrillation action is observed at therapeutic doses. The tone ofthe smooth muscle of the vessels is also greatly reduced. Thisvascular-spasmolytic action can be observed in the entire vascularsystem as well as in more or less isolated and circumscribed vascularregions such as the central nervous system. In addition, a strongmuscular-spasmolytic action is manifested in the smooth muscle of thestomach, the intestinal tract, the urogenital tract and the respiratorysystem. Finally, there is some evidence that the compounds influence thecholesterol level and lipid level of the blood. These effects complementone another and the compounds are thus highly desirable aspharmaceutical agents to be used in the treatment of hypertension andconditions characterized by a constriction of the coronary bloodvessels.

Pharmaceutical compositions for effecting such treatment will contain amajor or minor amount, e.g. from 95% to 0.5% of at least one compound ofthe present invention in combination with a pharmaceutical carrier, thecarrier comprising one or more solid, semi-solid or liquid diluent,filler and formulation adjuvant which is nontoxic, inert andpharmaceutically acceptable. Such pharmaceutical compositions arepreferably in dosage unit form; i.e., physically discrete unitscontaining a predetermined amount of the drug corresponding to afraction or multiple of the dose which is calculated to produce thedesired therapeutic response. The dosage units can contain one, two,three, four or more single doses, or, alternatively, one half, one thirdor one fourth of a single dose. A single dose preferably contains anamount sufficient to produce the desired therapeutic effect uponadministration at one application of one or more dosage units accordingto a predetermined dosage regimen, usually a whole, half, third orquarter of the daily dosage administered once, twice, three or fourtimes a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the daily dose will befrom about 0.01 to about 10 mg/kg, preferably 0.1 to 5 mg/kg, whenadministered parenterally and from about 1 to about 100 mg/kg,preferably 5 to 50 mg/kg, when administered orally. In some instances asufficient therapeutic effect can be obtained at lower doses while inothers, larger doses will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a nontoxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a nontoxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anon-toxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

Data relating to the coronary vessel dilation effect of compoundsrepresentative of those of the present invention is given below in TableI. The data was obtained by measuring the increase in oxygen saturationin the coronary sinus of narcotized, heart-catheterized mongrel dogs.

                  TABLE I                                                         ______________________________________                                                                         Return to.sup.4                                        Dose.sup.2 Rise in O.sub.2.sup.3                                                                     Normal O.sub.2                               Compound.sup.1                                                                          I.V.       Saturation  Values                                       ______________________________________                                        1         0.05       24          20                                           2         0.5        34          30                                           2a        0.1        32          20                                           3         0.5        46          60                                           4         0.5        26          30                                           6         0.5        32          60                                           8         0.5        27          45                                           15        0.01       28          30                                           16        0.05       33          60                                           17        0.02       26          30                                           24        0.5        24          30                                           25        0.3        20          30                                           27        0.1        20          60                                           29        0.5        26          >20                                          30        0.02       27          60                                           31        0.5        26          60                                           32        0.2        29          >120                                         33        0.5        24          45                                           37        0.5        23          20                                           43        0.3        24          30                                           ______________________________________                                         Notes                                                                         .sup.1 Compounds are identified by the number of the Preparative Example      describing their production.                                                  .sup.2 Expressed as mg/kg body weight.                                        .sup.3 Expressed as percentage rise in the oxygen saturation in the           coronary sinus.                                                               .sup.4 I. e., Time for oxygen saturation in coronary sinus to return to       its predosage value, expressed in minutes.                               

Preparative Examples EXAMPLE 1

2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-pyridyl)-methyl ester ##STR21##

A solution of 7.5 g of 2-nitrobenzaldehyde, 20 g of acetoacetic acidmethyl-β-pyridyl ester (boiling point at 0.5 mm Hg: 145°-150°) and 5ccs. of ammonia in 30 ccs. of methanol is heated to the boil for 3 hoursand evaporated, and after being taken up in acetone the product isprecipitated as the HCl salt using hydrochloric acid. Yield 80%.

Crystals of melting point 170° - 172° C are obtained from isopropanoland a little methanol.

EXAMPLE 2

2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(α-pyridyl)-methyl ester ##STR22##

After heating a solution of 7.5 g of o-nitrobenzaldehyde, 20 g ofacetoacetic acid methyl-α-pyridyl ester (boiling point at 0.5 mm Hg:138°-140°) and 10 ccs. of ammonia in 30 ccs. of methanol for 3 hours,the mixture is concentrated and taken up in acetone, and the HCl salt isprecipitated with hydrochloric acid in ether. Yield 90%.

After recrystallization from alcohol, canary-yellow crystals of meltingpoint 206° - 208° C are obtained.

In the same manner: a. 7.5 g of m-nitrobenzaldehyde, 20 g of acetoaceticacid methyl-α-pyridyl ester and 10 ccs. of ammonia in 30 ccs. ofmethanol yielded2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(α-pyridyl)-methyl ester as the hydrochloride, in yellowcrystals of melting point 152° - 155° C, yield 88%, and b. 7.5 g ofm-nitrobenzaldehyde, 20 g of acetoacetic acid methyl-β-pyridyl ester and10 ccs. of ammonia in 30 ml of methanol yielded2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-pyridyl)-methyl ester as the hydrochloride in yellow crystalsof melting point 202° - 204° C. Yield 85%.

EXAMPLE 3

2,6-dimethyl-4-(2'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-N-morpholino)-isopropyl ester ##STR23##

After heating a solution of 8.7 g of o-trifluoromethylbenzaldehyde, 23 gof acetoacetic acid β-morpholinoisopropyl ester (boiling point at 0.4 mmHg: 126°) and 5 ccs. of ammonia for several hours, the mixture isconcentrated in vacuo and taken up in acetone-ether, and thehydrochloric acid salt is obtained by hydrochloric acid in ether. Yield70%.

Light yellow crystals of melting point 220° C as alcohol acetone.

EXAMPLE 4

2,6-dimethyl-4-(3'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-pyridyl)-methyl ester ##STR24##

After heating 10 g of 3-trifluoromethyl-benzaldehyde and 25 g ofacetoacetic acid methyl-β-pyridyl ester (boiling point 0.1 mm Hg: 125°C) and 6 ccs. of ammonia in 60 ccs. of alcohol for several hours, whitecrystals of melting point 198° C were obtained. Yield 55%.

EXAMPLE 5

2,6-dimethyl-4-(4'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-N-morpholino)-ethyl ester. ##STR25##

14 g of 4-chlorobenzaldehyde, 43 g of acetoacetic acid β-morpholinoethylester (boiling point at 0.5 mm Hg: 128°-130° C) and 10 ccs. of ammoniain 100 ccs. of methanol are heated to the boil for 5 hours and themixture is filtered and concentrated in vacuo. It is taken up in etherand then precipitated as the hydrochloride with hydrochloric acid inether. Crystals of melting point 178° - 180° C from alcohol. Yield 76%.a. In the same manner, 17 g of 2,4-dichlorobenzaldehyde, 43 g ofacetoacetic acid β-morpholinoethyl ester and 10 ccs. of ammonia in 100ccs. of methanol yield,2,6-dimethyl-4-(2'-4'-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-N-morpholino)-ethyl ester as the hydrochloride, inyellow-green crystals of melting point 169° - 171° C. Yield 66%.

EXAMPLE 6

2,6-dimethyl-4-(3'-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-N-morpholino)-isopropyl ester. ##STR26##

After boiling a solution of 6.5 g of 3-cyanobenzaldehyde, 23 g ofacetoacetic acid 2-morpholino-isopropyl ester and 6 ccs. of ammonia for8 hours, the mixture is evaporated in vacuo and taken up inacetone-ether, and the product is precipitated as the HCl salt withhydrochloric acid. Yellow crystals of melting point 156° C. Yield 90%.

EXAMPLE 7

2,6-dimethyl-4-(4'-ethylsulphonylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(α-pyridyl)-methyl ester. ##STR27##

10 g of 4-ethylsulphonylbenzaldehyde, 5 ccs. of concentrated ammonia and19.5 g of acetoacetic acid (α-pyridyl)-methyl ester in 40 ccs. ofalcohol are heated under reflux for 8 hours. The mixture is concentratedin vacuo and after addition of ether crystals which melt at 138° C whenrecrystallized from alcohol are obtained. Yield 73%.

EXAMPLE 8

2,6-dimethyl-4-(3'-azidophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(βN-morpholino)-ethyl ester. ##STR28##

7.4 g of 3-azidobenzaldehyde, 23 g of acetoacetic acid 2-morpholinoethylester and 6 ccs. of ammonia in 30 ccs. of alcohol are heated to the boilovernight and after precipitation with hydrochloric acid in ether theHCl salt of melting point 183° C (alcohol/light beige) is obtained.Yield 69%.

EXAMPLE 9

2,6-dimethyl-4-(4'-dimethylaminophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-pyridyl)-methyl ester. ##STR29##

After heating 7.5 g of 4-dimethyl-aminobenzaldehyde, 20 g of acetoaceticacid methyl-β-pyridyl ester and 5 ccs. of ammonia in 30 ccs. of methanolfor 3 hours, and concentrating the mixture, crystals of melting point166° - 168° C are obtained. Yield 43%.

EXAMPLE 10

2,6-dimethyl-4-(α-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddi-(α-pyridyl)-methyl ester. ##STR30##

A solution of 5.3 g of pyridin-2-aldehyde, 20 g of acetoacetic acidmethyl-α-pyridyl ester and 6 ccs. of ammonia in 100 ccs. of alcohol isheated to the boil for 7 hours and after evaporation crystals(yellowish) of melting point 146° - 148° C are obtained from alcohol.Yield 39%.

EXAMPLE 11

2,6-dimethyl-4-(3'-nitro-6'-methylmercaptophenyl)-1,4-dihydro-3,5-dicarboxylicacid di-(β-pyridyl)-methyl ester. ##STR31##

10 g of 3-nitro-6-methylmercaptobenzaldehyde (melting point 163° C), 20g of acetoacetic acid methyl-β-pyridyl ester and 6 ccs. of ammonia in 80ccs. of alcohol are heated to the boil for several hours, the mixture isfiltered hot after addition of charcoal and is concentrated, and theresidue is recrystallized from 200 ccs. of acetone.

Yellow crystals of melting point 182° - 184° C. Yield 52%.

EXAMPLE 12

2,6-dimethyl-4(4',6'-dimethoxy-5-pyrimidyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-N-morpholino)-isopropyl ester. ##STR32##

8.4 g of 4,6-dimethoxy-pyrimidin-5-aldehyde, 23 g of acetoacetic acidβ-morpholinoisopropyl ester and 5 ccs. of ammonia in 30 ccs. of methanolare heated to the boil for several hours, the mixture is evaporated andtaken up in acetone and the product is precipitated as the hydrochloridewith hydrochloric acid in ether.

Beige crystals of melting point 216° - 218° C from alcohol. Yield 47%.

EXAMPLE 13

1,2,6-trimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic aciddi-(β-N-morpholino)-isopropyl ester. ##STR33##

5 g of benzaldehyde, 23 g of acetoacetic acid 2-morpholino-isopropylester and 4 g of methylamine hydrochloride in 25 ccs. of pyridine areheated to about 90° C for 6 hours; the mixture is introduced into icewater and taken up in ether, and after washing with water and dryingover sodium sulphate, hydrochloric acid in ether yields the HCl salt inyellow crystals of melting point 159° C. Yield 75%.

EXAMPLE 14

1,2,6-trimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(β-N-morpholino)-isopropyl ester. ##STR34##

7.5 g of 2-nitrobenzaldehyde, 23 g of acetoacetic acidβ-morpholino-isopropyl ester and 4 g of methylamine hydrochloride in 40ccs. of pyridine are allowed to stand for 3 hours at 90° C; the mixtureis introduced into ice water and taken up in ether, the ether solutionis washed with water and dried over sodium sulphate and the product isprecipitated as the hydrochloride with hydrochloric acid in ether.Yellow crystals of melting point 168° - 170° C. Yield 61%.

EXAMPLE 15

2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR35##

A solution of 7.5 g of o-nitrobenzaldehyde, 9.7 g of acetoacetic acid(α-pyridyl)-methyl ester, and 6 g of β-aminocrotonic acid methyl esterin 40 ccs. of alcohol is heated to the boil for several hours and theproduct is filtered off.

Yellow crystals (alcohol) of melting point 196° C. Yield 65%.

EXAMPLE 16

2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-isopropyl ester. ##STR36##

7.5 g of o-nitrobenzaldehyde, 9.7 g of acetoacetic acid(α-pyridyl)-methyl ester and 7.2 g of β-aminocrotonic acid isopropylester in 40 ccs. of alcohol are heated to the boil overnight and aftercooling, filtration and rinsing with alcohol and ether ochre-yellowcrystals of melting point 175° C are obtained. Yield 70%.

EXAMPLE 17

2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methoxyethyl ester. ##STR37##

After heating a solution of 7.5 g of 2-nitrobenzaldehyde, 9.7 g ofacetoacetic acid (α-pyridyl)-methyl ester and 8 g of β-aminocrotonicacid β-methoxyethyl ester in 40 ccs. of alcohol for several hours,yellow crystals of melting point 123° C are obtained. Yield 55%.

EXAMPLE 18

2,6-dimethyl-4-(2'-trifluoromethyl-4'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR38##

After heating a solution of 11 g of2-trifluoromethyl-4-nitrobenzaldehyde, 9.7 g of acetoacetic acidmethyl-α-pyridyl ester and 6 g of β-aminocrotonic acid methyl ester in40 ccs. of alcohol for several hours, yellow crystals of melting point155° C are obtained (on cooling). Yield 55%.

EXAMPLE 19

2,6-dimethyl-4-(3'-fluoro-4'-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(β-morpholino)-ethyl ester 5-methyl ester. ##STR39##

After heating a solution of 7.7 g of 3-fluoro-4-methoxybenzaldehyde, 11g of acetoacetic acid β-morpholinoethyl ester and 6 g of β-aminocrotonicacid methyl ester in 40 ccs. of alcohol for several hours, the mixtureis evaporated in vacuo, the residue is taken up in ether and the productis precipitated as the hydrochloride with hydrochloric acid in ether.

The free compound is obtained from the yellow hydrochloric acid salt aswhite crystals of melting point 105° C (benzene/petroleum ether). Yield75% (HCl salt).

EXAMPLE 20

2,6-dimethyl-4-(4',6'-dimethoxy-5-pyrimidyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR40##

A solution of 5 g of 4,6-dimethoxypyrimidin-5-aldehyde, 5.9 g ofacetoacetic acid α-pyridyl-methyl ester and 3.6 g of β-aminocrotonicacid methyl ester in 30 ccs. of alcohol is heated to the boil for 8hours and the free compound is obtained, via the HCl salt (light yellowcrystals) as white crystals of melting point 57° - 58° C. Yield 84%.

EXAMPLE 21

2,6-dimethyl-4-(4'-acetaminophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 3-methyl ester. ##STR41##

8.2 g of 4-acetaminobenzaldehyde, 9.7 g of acetoacetic acid(α-pyridyl)-methyl ester and 6 g of β-aminocrotonic acid methyl ester in40 ccs. of alcohol are heated to the boil for 4 to 6 hours andconcentrated, and, after addition of ether and cooling, yellow crystalsof melting point 199° C are obtained. Yield 75%.

EXAMPLE 22

2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-N-N'-methylpiperazino)-propyl ester 5-methyl ester. ##STR42##

After heating a solution of 7.5 g of o-nitrobenzaldehyde, 12 g ofacetoacetic acid (γ-N-N'-methylpiperazino)-n-propyl ester (boiling point140° C at 1 mm Hg) and 6g of β-aminocrotonic acid methyl ester in 40ccs. of alcohol for several hours, the mixture is concentrated and takenup in ether and the product is precipitated as the hydrochloride withhydrochloric acid in ether and recrystallized from alcohol. Light yellowcrystals of melting point 240° C. Yield 75%.

EXAMPLE 23

1,2,6-trimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(β-diethylamine)-ethyl ester 5-methyl ester. ##STR43##

11 g of1,2,6-trimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid-5-carboxylic acid methyl ester (melting point 166°) and 7 ccs. ofdiethyl-(2-chloroethyl)-amine in 200 ccs. of isopropyl alcohol areheated overnight; the mixture is filtered and the reaction product isobtained as the hydrochloride (precipitation with hydrochloric acid) incrystals of melting point 178° - 180° C (page beige). Yield 65%.

EXAMPLE 24

2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid3-(β-N-morpholino)-ethyl ester 5-ethyl ester. ##STR44##

After heating a solution of 5 ccs. of benzaldehyde, 11 g of acetoaceticacid (β-N-morpholino)-ethyl ester and 6 g of β-aminocrotonic acid methylester in 40 ccs. of alcohol for several hours, the mixture isconcentrated and after taking up in ether, the hydrochloride salt isprecipitated with hydrochloric acid. Yellow crystals, yield 80%.

The free compound is obtained as white crystals of melting point 112° C(benzene-petroleum ether).

EXAMPLE 25

2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR45##

5 ccs. of benzaldehyde, 9.7 g of acetoacetic acid (α-pyridyl)-methylester and 6 g of β-aminocrotonic acid methyl ester in 40 ccs. of alcoholare heated to the boil for several hours, the mixture is concentratedand the product is precipitated as the HCl salt with hydrochloric acid.Light yellow crystals, yield 85%.

EXAMPLE 26

2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid3-(γ-N-N'-methylpiperazino)-n-propyl ester 5-carboxylic acid methylester. ##STR46##

After heating a solution of 5 ccs. of benzaldehyde, 12 g of acetoaceticacid (γ-N-N'-methylpiperazino)-n-propyl ester and 6 g of β-aminocrotonicacid methyl ester in 40 ccs. of alcohol under reflux for several hours,yellow crystals are obtained as the HC1 salt after working up as abovedescribed. Yield 90%.

EXAMPLE 27

2,6-dimethyl-4-(2'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR47##

7 g of 2-chlorobenzaldehyde, 9.7 g of acetoacetic acid(α-pyridyl)-methyl ester and 6 g of β-aminocrotonic acid methyl ester in40 ccs. of alcohol are heated to the boil for 4 to 6 hours andconcentrated, the residue is taken up in ether and the HCl salt isprecipitated with hydrochloric acid in ether. Yellow crystals, 85%yield.

EXAMPLE 28

2,6-dimethyl-4-(2'-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-N,N'-methylpiperazino)-methyl ester 5-methyl ester. ##STR48##

7 g of 2-chlorobenzaldehyde, 12 g of acetoacetic acid(γ-N,N'-methylpiperazino)-methyl ester and 6 g of β-aminocrotonic acidmethyl ester in 60 ccs. of alcohol are heated to the boil overnight andfinally concentrated, the residue is taken up in ether and the productis precipitated as the hydrochloride salt with hydrochloric acid. Yellowcrystals, yield 75%.

EXAMPLE 29

2,6-dimethyl-4-(2'-azidophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR49##

A solution of 7.4 g of 2-azidobenzaldehyde, 9.7 g of acetoacetic acid(α-pyridyl)-methyl ester and 6 g of β-aminocrotonic acid methyl ester in40 ccs. of alcohol is heated to the boil for approximately 6 hours,concentrated and treated with ether and subsequently with hydrochloricacid in ether. The hydrochloride salt is precipitated as ochre yellowcrystals, yield 75%.

EXAMPLE 30

2,6-dimethyl-4-(2'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR50##

After heating a solution of 8.7 g of 2-trifluoromethyl-benzaldehyde, 6 gof β-aminocrotonic acid methyl ester and 9.7 g of acetoacetic acid(α-pyridyl)-methyl ester in 40 ccs. of alcohol for several hours andconcentrating the mixture is taken up in ether and the reaction productis precipitated as the hydrochloride salt with hydrochloric acid. Yellowcrystals, yield 75%.

EXAMPLE 31

2,6-dimethyl-4-(2'-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-N,N'-methylpiperazino)-n-propyl ester 5-methyl ester.##STR51##

8.7 g of 2-trifluoromethylbenzaldehyde, 12 g of acetoacetic acid(γ-N,N'-methylpiperazino)-n-propyl ester and 6 g of β-aminocrotonic acidmethyl ester in 40 ccs. of alcohol are heated to the boil overnight andafter concentration the product is precipitated as the HCl salt withhydrochloric acid. Yellow crystals, yield 75%.

EXAMPLE 32

2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(β-N-morpholino)-ethyl ester 5-methyl ester. ##STR52##

A solution of 7.5 g of 3-nitrobenzaldehyde, 11 g of acetoacetic acid(β-N-morpholino)-ethyl ester and 6 g of β-aminocrotonic acid methylester in 40 ccs. of alcohol is heated to the boil overnight andconcentrated, and the HCl salt is precipitated with hydrochloric acid.Light yellow crystals, yield 90%.

EXAMPLE 33

2,6-dimethyl-4-(3'-nitrophenyl)1,4-dihydropyridine-3,5-dicarboxylic acid3-(γ-N,N'-methylpiperazino)-n-propyl ester 5-methyl ester. ##STR53##

After heating a solution of 7.5 g of 3-nitrobenzaldehyde, 12 g ofacetoacetic acid (γ-N,N'-methylpiperazino)-n-propyl ester and 6 g ofβ-aminocrotonic acid methyl ester in 40 ccs. of alcohol for 6 hours, themixture is concentrated and taken up in ether and the product isprecipitated as the HCl with hydrochloric acid. Ochre-yellow crystals,yield 65%.

EXAMPLE 34

2,6-dimethyl-4-(4'-mercaptophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(β-N-morpholino)-ethyl ester 5-methyl ester. ##STR54##

After heating a solution of 7.6 g of 4-mercaptobenzaldehyde, 10.8 g ofacetoacetic acid (β-N-morpholino)-ethyl ester and 6 g of β-aminocrotonicacid methyl ester in 40 ccs. of alcohol for several hours, the mixtureis concentrated and taken up in ether and the HCl salt is precipitatedwith hydrochloric acid in ether. Light yellow crystals, yield 85%.

EXAMPLE 35

2,6-dimethyl-4-(α-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-(β-N-morpholino)-isopropyl ester 5-methyl ester. ##STR55##

After heating a solution of 10.5 ccs. of α-pyridinaldehyde, 23 g ofacetoacetic acid (β-N-morpholino)-isopropyl ester and 13 g ofβ-aminocrotonic acid methyl ester in 80 ccs. of alcohol to the boil forseveral hours, the mixture is concentrated and taken up in ether and theproduct is precipitated as the hydrochloride with hydrochloric acid inether. Ochre-yellow crystals, yield 90%.

EXAMPLE 36

2,6-dimethyl-4-(2'-bromo-5'-furyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR56##

8.8 g of 5-bromo-furfurol, 9.7 g of acetoacetic acid (α-pyridyl)-methylester and 6 g of β-aminocrotonic acid methyl ester in 40 ccs. of alcoholare heated to the boil overnight. After working up and precipitation,the HCl is obtained with hydrochloric acid as light yellow crystals.Yield 70%.

EXAMPLE 37

2,6-dimethyl-4-(2'-nitro-5-thenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR57##

7.9 g of 5-nitrobenzaldehyde, 9.7 g of acetoacetic acid(α-pyridyl)-methyl ester and 6 g of β-aminocrotonic acid methyl ester in40 ccs. of alcohol are heated to the boil for 10 hours. The HCl salt isobtained with hydrochloric acid in ochre-yellow crystals, yield 75%.

EXAMPLE 38

1,2,6-trimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(α-pyridyl)-methyl ester 5-methyl ester. ##STR58##

13 g of 3'-nitrophenylbenzylideneacetoacetic acid methyl ester (meltingpoint 105° C), 9.7 of acetoacetic acid (α-pyridyl)-methyl ester and 4gof methylamine hydrochloride in 40 ccs. of pyridine are heated to about90° C for 2 to 3 hours, the mixture is introduced into water andextracted with ether, and after washing and drying the product isprecipitated as the hydrochloride with hydrochloric acid in ether.Ochre-yellow crystals, yield 76%.

EXAMPLE 39

1,2,6-trimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-N,N'-methylpiperazino)-n-propyl ester 5-methyl ester.##STR59##

12.5 g of 3-nitrophenylbenzylideneacetoacetic acid methyl ester, 12 g ofacetoacetic acid (γ-N,N'-methylpiperazino)-n-propyl ester and 4 g ofmethylamine hydrochloride in 40 ccs. of pyridine, are heated to about90° C for 5 hours. Thereafter the mixture is introduced into water/iceand decanted, the residue is taken up in ether, and after washing anddrying the solvent is distilled off. Yellow crystals of melting point131° C from ether/petroleum ether. Yield 27%.

EXAMPLE 40

2,6-dimethyl-4-(4'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(β-N-morpholino)-ethyl ester 5-methyl ester. ##STR60##

After heating a solution of 15 g of 4-nitrobenzaldehyde, 11 g ofacetoacetic acid (β-N-morpholino)-ethyl ester and 6 g of aminocrotonicacid methyl ester in 40 ccs. of alcohol under reflux for several hours,light yellow crystals are obtained as the HCl salt with hydrochloricacid. Yield 75%.

EXAMPLE 41

2,6-dimethyl-4-styryl-1,4-dihydropyridine-3,5-dicarboxylic acid3-γ-N,N'-methylpiperazino)-propyl ester 5-methyl ester. ##STR61##

6.6 g of cinnamaldehyde, 6 g of β-aminocrotonic acid methyl ester and 12g of acetoacetic acid (γ-N,N'-methylpiperazino)-propyl ester in 40 ccs.of ethanol are heated to the boil overnight and after concentration thehydrochloric acid salt is precipitated from the solution of hydrochloricacid in ether. Orange crystals, yield 70%.

EXAMPLE 42

2,6-dimethyl-4-(β-phenyl-ethyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-N,N'-methylpiperazino)-propyl ester 5-methyl ester. ##STR62##

A solution of 6.7 g of hydrocinnamaldehyde, 12 g of acetoacetic acid(γ-N,N'-methylpiperazino)-propyl ester and 6 g of β-aminocrotonic acidmethyl ester in 40 ccs. of ethanol is heated to the boil for 5 to 6hours and after concentration the reaction product is precipitated asthe hydrochloric acid salt with hydrochloric acid. Yellow crystals,yield 55%.

EXAMPLE 43

2,6-dimethyl-4-(3'-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-N,N'-methylpiperazino)-propyl ester 5-methyl ester. ##STR63##

A solution of 6.8 g of 3-methoxybenzaldehyde, 5.8 g of β-aminocrotonicacid methyl ester and 12 g of acetoacetic acid(γ-N,N'-methylpiperazino)-propyl ester in 40 ccs. of ethanol is heatedto the boil overnight and evaporated and after addition of ether thereaction product is precipitated as the hydrochloric acid salt. Lightyellow crystals, yield 45%.

EXAMPLE 44

2,6-dimethyl-4-(4'-quinolyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-(γ-N,N'-methylpiperazino)-propyl ester 5-methyl ester. ##STR64##

After heating a solution of 7.9 g of quinolin-4-aldehyde, 12 g ofacetoacetic acid (γ-N,N'-methylpiperazino)-propyl ester and 5.8 g ofβ-aminocrotonic acid methyl ester in 40 ccs. of ethanol under reflux for8 hours the mixture is evaporated and taken up in ether and the productis precipitated as the hydrochloride with hydrochloric acid in ether.Yellow crystals, yield 65%.

EXAMPLE 45

2,6-dimethyl-4-(α-naphthyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-(γ-N,N'-methylpiperazino)-propyl ester 5-methyl ester. ##STR65##

8 g of α-naphthaldehyde, 12 g of acetoacetic acid(γ-N,N'-methylpiperazino)-propyl ester and 5.8 g of β-aminocrotonic acidmethyl ester in 40 ccs. of alcohol are heated to the boil for severalhours and evaporated, the residue is taken up in ether and the reactionproduct is precipitated as the hydrochloride salt with hydrochloricacid. Light yellow crystals, yield 60%.

EXAMPLE 46

1-isopropyl-2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di(γ-N,N'-methylpiperazino)-propyl ester. ##STR66##

A solution of 7.5 g of 3-nitrobenzaldehyde, 3 g of isopropylamine and24.5 g of acetoacetic acid (γ-N,N'-methylpiperazino)-propyl ester in 40ccs. of ethanol is heated to the boil overnight and subsequentlyevaporated, and after addition of ether the product is precipitated asthe hydrochloride salt with hydrochloric acid. Yellow crystals, yield60%.

EXAMPLE 47

1-n-Butyl-2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid di-(γ-N,N'-methylpiperazino)-propyl ester. ##STR67##

A solution of 7.5 g of 3-nitrobenzaldehyde, 4 g of n-butylamine and 24.2g of acetoacetic acid (γ-N,N'-methylpiperazino)-propyl ester in 40 ccs.of ethanol is heated overnight under a reflux condenser and evaporated,and the hydrochloride salt is precipitated from the solution ofhydrochloric acid in ether. Yellow crystals, yield 65%.

EXAMPLE 48

1,2,6-trimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-dimethylamino)-propyl ester 5-ethyl ester. ##STR68##

18 g of1,2,6-trimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3-carboxylicacid-5-carboxylic acid ethyl ester (melting point 167° C) in 180 ccs. ofethanol are heated to the boil, a solution of 1.15 g of sodium in 50ccs. of ethanol is next added, followed by 7.5 g ofγ-dimethylamino-propyl chloride (dropping funnel), and the mixture iskept at the boil for several hours. After evaporation, the residue istaken up in ether, the ether is evaporated and the yellow reactionproduct (yield 95%) is recrystallized from ligroin. White crystals ofmelting point 103° C are obtained.

What is claimed is:
 1. A compound of the formula: ##STR69## or apharmaceutically acceptable nontoxic salt thereof wherein R is hydrogen,straight- or branched-chain lower alkyl, alkenyl of 2 to 4 carbon atomsor alkynyl of 2 to 4 carbon atoms;R¹ and R⁴ are the same or differentand are each hydrogen or straight- or branched-chain lower alkyl; X isstraight- or branched-chain lower alkylene; Y is the moiety NR'R"wherein R' and R" are the same or different and are each hydrogen orlower alkyl; R² is phenyl substituted by 1, 2 or 3 substituents selectedfrom the group consisting of nitro, lower alkyl, lower alkoxy, phenyl,trifluoromethyl and halogen; benzyl; phenyl-ethyl; or naphthyl; and R³is the moiety -OQ wherein Q is straight, branched or cyclic, saturated,partially unsaturated or unsaturated lower alkyl unsubstituted orsubstituted by one or two hydroxyl groups, alkoxyalkyl of up to 6 carbonatoms in both moieties or the moiety -O-X'-Y' wherein X' is straight- orbranched-chain lower alkylene and Y' is the moiety NR'R" wherein R' andR" are the same or different and are are each hydrogen or lower alkyl.2. A compound according to claim 1 whereinR is hydrogen, straight- orbranched-chain alkyl of 1 to 4 carbon atoms or straight- orbranched-chain alkenyl of 2 to 4 carbon atoms; R¹ and R⁴ are the same ordifferent and are each hydrogen or straight- or branched-chain alkyl of1 to 4 carbon atoms; X is straight- or branched-chain alkylene of 1 to 4carbon atoms; Y is the moiety NR'R" wherein R' and R" are the same ordifferent and are each hydrogen or alkyl of 1 to 4 carbon atoms; R² isphenyl substituted by 1 to 2 nitro, alkyl of 1 to 4 carbon atoms,chloro, bromo or trifluoromethyl, or by 1 to 3 alkoxy moieties of 1 to 4carbon atoms; benzyl; phenyl-ethyl; or naphthyl; and R³ is the moiety-OQ wherein Q is straight- or branched-chain alkyl of 1 to 4 carbonatoms, or alkoxyalkyl of up to 6 carbon atoms in both moieties, or themoiety -O-X'-Y' whereinX' is straight- or branched-chain alkylene of 1to 4 carbon atoms, and y' is the moiety NR'R" wherein R' and R" are asabove defined.
 3. A compound according to claim 1 wherein the alkylmoiety of R has 1 to 3 carbon atoms and the alkyl moiety of R¹ and R⁴has 1 or 2 carbon atoms.
 4. A compound according to claim 3 whereinR² isphenyl substituted by 1 or 2 alkyl moieties of 1 or 2 carbon atoms, 1 to3 alkoxy moieties of 1 or 2 carbon atoms or 1 or 2 members selected fromthe group consisting of nitro, chloro, bromo and trifluoromethyl;benzyl; phenyl-ethyl; or naphthyl; and R³ is the moiety -OQ whereinQ isstraight- or branched-chain alkyl of 1 to 4 carbon atoms interrupted by1 oxygen atom or the moiety -O-X'-Y' whereinX' is straight- orbranched-chain alkylene of 1 to 4 carbon atoms, and y' is the moietyNR'R" wherein R' and R" are the same or different and are each hydrogenor alkyl of 1 to 4 carbon atoms.
 5. A compound according to claim 1whereinR is hydrogen or straight- or branched-chain alkyl of 1 to 4carbon atoms, R¹ and R⁴ are the same or different and are each straight-or branched-chain alkyl of 1 to 4 carbon atoms, X is straight- orbranched-chain alkylene of 1 to 4 carbon atoms, Y is dimethylamino, ordiethylamino; R² is phenyl substituted by 1 or 2 substituents selectedfrom the group consisting of nitro, chloro and trifluoromethyl, or by 1to 3 methoxy groups; or naphthyl; and R³ is the moiety -OQ wherein Q isstraight- or branched-chain alkyl of 1 to 4 carbon atoms, ormethoxyethyl.
 6. A compound according to claim 1 whereinR is hydrogen orstraight- or branched-chain alkyl of 1 to 4 carbon atoms, R¹ isstraight- or branched-chain alkyl of 1 to 3 carbon atoms, R⁴ isstraight- or branched-chain alkyl of 1 to 4 carbon atoms, X is straight-or branched-chain alkylene of 1 to 3 carbon atoms, Y is dimethylamino,or diethylamino, R² is phenyl substituted by nitro, nitro andtrifluoromethyl, nitro and chloro, dinitro, trifluoromethyl,ditrifluoromethyl, chloro, dichloro, methoxy, methoxy and fluoro,trimethoxy, or fluoro; or naphthyl; and R³ is straight- orbranched-chain alkoxy of 1 to 4 carbon atoms, or methoxyethyl.
 7. Thecompound according to claim 1 which is1,2,6-trimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(β-diethylamine)-ethyl ester 5-methyl ester or the hydrochloridesalt thereof.
 8. The compound according to claim 1 which is1,2,6-trimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-(γ-dimethylamino)-propyl ester 5-ethyl ester.